This application seeks funding for a multi-reservation randomized controlled trial (RCT) of a popular, widely disseminated, substance abuse prevention program targeted at Anishinabe (Ojibwe) preadolescents aged 8-10 years, their parents/caretakers, and extended family adults who have daily influence over the target child's behaviors. The Bii-Zin-Da-De-Dah (BZDDD) (Listening to One Another) program was the first American Indian (AI) adaptation of the Iowa Strengthening Families Program. Now in its third generation, BZDDD has been adapted for Dakota, Lakota, Pueblo, and Navajo cultures and is currently the center piece of a Canadian national Indigenous mental health promotion funded by Public Health Agency of Canada. Although BZDDD has been extremely popular at the grassroots level and has been adapted to numerous cultures there has never been a large-scale empirical evaluation of the program's efficacy for reducing adolescent alcohol and drug use. Our overall goal is to implement a RCT of a fourth-generation BZDDD prevention program that can be replicated cross-culturally by other North American Indigenous cultures to decrease substance use among early adolescents and improve mental health outcomes. This goal will be accomplished through four specific aims: 1) Complete a final adaptation of the 14-week BZDDD prevention program for the U.S. reservations; 2) Implement a RCT of BZDDD to assess its efficacy for delaying and/or preventing adolescent onset of alcohol and drug use; 3) Empirically address cultural challenges for RCTs involving Indigenous cultures by evaluating contamination and informal diffusion in communities and extended families; and 4) Work with our Anishinabe research partners to develop a plan to sustain the prevention. Using intent to treat design, the RCT will involve 255 treatment and 255 waitlist control families who live on or near five Anishinabe reservations in Minnesota and Wisconsin. There will be a pretest and initial post-test, with subsequent 6, 12, 18, 24, 30, and 36 month follow-ups, thus evaluating the target children through the critical years of substance use initiation. The proposed RCT will leave behind an empirically-based, family-centered prevention program that is easily woven into existing tribal social and health services or school settings. It also will be a template for adaptation to other Indigenous cultures.